The scope of the present invention is broad, incorporating: novel anion exchange materials, novel support materials for affinity or ion chromatographic materials, methods for producing the anion exchange materials, methods for removing species from biological fluids such as whole blood, improved methods for processing blood extracorporeally and methods of medical treatment. In one embodiment of the invention there is disclosed an extracorporeal treatment process for removing heparin from whole blood by passing the heparin containing blood through a filter device containing the biocompatible anion exchange material of the present invention.
There are a wide number of applications where it is desirable to remove anionic (negatively charged) species or chemicals from whole blood. For example, anionic exchange materials--supports that have cationic or positively charged surfaces--have been suggested for the removal of barbiturates in drug overdose cases, bilirubin from jaundiced patients and heparin for the prevention of post-operative bleeding. See, e.g., Cipoletti, et al., Resin Technology in Medicine in Sorbents and Their Clinical Applications, Giordano ed., Academic Press, New York, 1980; Sideman et al., Contr. Nephrol., 29:90-100, 1982; U.S. Pat. No. 4,800,016 of Yang; Matsuda et al., Art Organs, 13:504-7, 1989; Hov et al., Art Organs., 14:436-442, 1990.
Supported cationic surfaces have also been suggested for the use of the removal of coagulation factors at polymer surfaces for reduced thrombogenicity and improved biocompatibility. See, Wilson, Drug Dev. Res., 21:79-92, 1990.
Despite the promise of such techniques, the use of anionic exchange materials in whole blood applications has been limited by the biocompatability of the materials used. With the materials used to date, all researchers have noticed a demonstrable removal of platelets--and to a lesser extent white blood cells--from the whole blood samples passed over anion exchange supports. Previous attempts have been made to coat or shield the cation on the surface of the support materials in order to prevent the removal of blood components while retaining the ability to associate with anionic species in the whole blood sample. Such attempts have led to reductions in efficiency and/or capacity to remove anionic species from the whole blood. This is especially true where the anionic species that are being removed from the blood are relatively large (heparin, coagulation factors, etc.)
The use of the anionic exchange materials of the present invention need not be limited to the removal of anionic species. The biocompatible material can be further modified to yield chromatographic materials that rely on affinity interactions.
U.S. patent application Ser. No. 07/562,009 (the '009 Application) is commonly assigned with the present application. In the '009 Application, a method of medical treatment is described wherein a medical agent is administered to a patient, and after a period of time the medical agent is removed extracorporeally by passing body fluid over a support adopted to immobilize the agent. Several embodiments of the present invention are adaptable for use in the method described in the '009 Application due to the biocompatability of the anion exchange materials disclosed herein.
In one such embodiment, and in variations thereof, it is desirable to remove heparin from whole blood. Extracorporeal circulation of blood--required in many surgical and medical procedures--requires the use of systemic heparin to prevent coagulation. Heparin is a highly negatively charged compound. In almost all cases it is necessary to neutralize or remove the heparin in the patient's blood prior to the completion of the surgical procedure. This is required to prevent post-operative bleeding complications. The most commonly used means for neutralizing heparin in this situation is by treatment with protamine sulfate. Unfortunately, the administration of protamine sulfate has several adverse side affects.
Other efforts to remove heparin from whole blood have been investigated. For example, U.S. Pat. No. 4,373,023 of Langer describes a support on which heparinase has been immobilized, an enzyme that degrades heparin. Others have attempted to use supported or immobilized protamine for heparin removal. See U.S. Pat. No. 4,800,016 of Yang; and Hou et al., Art Organs., 14:436-442, 1990.
Affinity or ion exchange chromatography allows purification or separation of most chemicals based on the molecules biological function or chemical structure. The separation process occurs because of variations in affinity between the individual members of a mixture of components to a ligand or reactive group which is immobilized on an insoluble support or substrate. The substrates used in affinity chromatography generally are openly porous, have large surface areas, and contain some functionality that can be easily modified for the introduction of ligands. See, for example, Dean & Johnson, Affinity Chromatography: a Practical Approach, IRL Press, Oxford, 1985. The support materials preferably are strong, relatively heat insensitive, and preferably do not grow or "swell" significantly when in solution.
A common substrate or support is agarose beads, which possess a high degree of surface hydroxyl groups (--OH). The hydroxyl group is ideal for support materials due to its ability to be easily converted to other reactive functionalities such as aldehydes, or to be directly reacted with desired ligands. Ion exchange materials configured as flat, flexible sheets have found widespread use as support materials due to their physical characteristics and ease of use. See, for example, U.S. Pat. No. 4,663,163 of Hou. The sheet supports are commercially available with a variety of reactive groups such as an aldehyde functionality. The ion exchange materials of the present invention are prepared by the simultaneous or serial treatment of a support material with chemicals that place both quaternary ammonium functionalities and polyethylene oxide units on the surface of the support. The anion exchange materials as disclosed herein are capable of retaining their anion exchange capabilities while also being biocompatible with the components of whole blood. In a preferred embodiment, the anion ion exchange material is used to remove heparin from whole blood.
Efforts to make affinity or chromatographic materials biocompatible have been made in the past. The use of polyethylene oxide moieties on the surface of the materials to increase biocompatibility to surfaces for certain purposes has been described. See, U.S. Pat. No. 4,424,311 of Nagoaka et al; and U.S. Pat. No. 4,678,468 of Hiroyoshi. It has been shown that the ability to confer biocompatibility is proportional to the chain length of the polymer units attached to the surface of the support. See, e.g., Mori et al., Trans Am Soc Artif Inter Organs, 28:459-463, 1982; Andvade et al., Trans Am Soc Artif Intern Organs, 33:75-84, 1987.
Other researches have used quaternary ammonium chemicals to ionically bind an antithrombic agent to a surface. In U.S. Pat. No. 4,678,660 of McGary, et al., heparin was complexed with the quaternary compound tridodecyl methyl ammonium chloride and incorporated into polyurethane. In U.S. Pat. No. 4,690,973 of Noishiki et al., glycidyl trimethyl ammonium chloride (GTMAC) was reacted with collagen, and heparin was immobilized on the surface.
Despite the desirability of obtaining biocompatible anion exchange materials, the prior art does not describe any attempt to include immobilized cationic species and polyethylene oxides in such a way to obtain the materials disclosed herein.
In a further reference, a heparin/hydrogel coating was described as a method of improving the biocompatability of activated carbon for hemoperfusion. See, U.S. Pat. No. 4,048,064 of Clark. Macroreticular resin material or coated activated charcoal may also be used in the disclosed process and produce biocompatible hemoperfusion materials.